In the modern era of highly active antiretroviral therapy (HAART), reluctance to perform transplantation (Tx) in HIV-infected individuals is no longer justified. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs), the current first line regimens of HAART, are metabolized by the cytochrome P450 family (CYP3A4). Most NNRTIs induce CYP3A4, whereas PIs inhibit it. Calcinuerin inhibitors (CNIs), which are mandatory for Tx, need the same enzyme complex for their clearance. Therefore, a significant drug-drug interaction (DDI) is encountered between current HAART and CNIs. This results in extreme difficulty in adjusting the optimal dose of CNIs, for which the therapeutic range is narrow. Of interest, integrase inhibitors (INIs) – novel, potent anti-HIV drugs – are mainly metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and do not induce or inhibit CYP3A4. DDI is presumably absent when NNTRIs or PIs are replaced by INIs. Raltegravir (RAL), a first generation INI, has been introduced into kidney and liver Tx. There is increasing evidence that rejection is well controlled without renal impairment due to CNI over-exposure while persistent, robust suppression of HIV is achieved. Global phase III clinical trials of dolutegravir (DTG), a second generation INI, are currently in progress. In vitro data has suggested that DTG may be less prone to resistance than RAL (referred to as having a higher genetic barrier). The time has come to extensively discuss the implications of INIs in Tx for HIV positive patients.
Riccardin F and pakyonol, macrocyclic bisbibenzyls from Plagiochasm intermedium, have been confirmed to possess antifungic activities against Candida albicans. Herein, we evaluated their anti-tumor activity in vitro by employing K562 and K562/A02 cells, the well-known adriamycin (ADR)-induced multidrug resistance (MDR) tumor cell lines over-expressing P-glycoprotein (P-gp). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assays showed that riccardin F and pakyonol ranging from 0 to 6 μg/mL exhibited no inhibitory effects on the growth of the two cell lines. However, in the presence of 3 μg/mL riccardin F or pakyonol (non-cytotoxic concentration), the IC50 of ADR against K562/A02 cells decreased by 2.51- and 4.78-fold, respectively. Flow cytometry showed that riccardin F and pakyonol significantly enhanced the accumulation of ADR in K562/A02 cells. Furthermore, fluorescence intensity detection revealed that the two natural products remarkably increased the retention of rhodamine-123 in K562/A02 cells rather than in K562 cells, indicating that the major cause for riccardin F and pakyonol to reverse P-gp-mediated MDR in K562/A02 cells is probably due to the constrained transport activity of P-gp. This study explores the potential application of bisbibenzyl type compounds as modulators of P-gp-mediated MDR in tumor cells.
A high-carbohydrate low-fat (HC/LF) diet and lipoprotein lipase gene (LPL) Ser447Stop and Hind III polymorphisms have separately been found to be associated with triacylglycerol (TG) and high density lipoprotein cholesterol (HDL-C). This study sought to test the effects of LPL polymorphisms and an HC/LF diet on the serum lipid profile of Chinese with a lower incidence of coronary artery disease (CAD) consuming a diet with less fat and more carbohydrates. Fifty-six healthy subjects (22.89 ± 1.80 years) were given a control diet of 30.1% fat and 54.1% carbohydrates for 7 days, followed by an HC/LF diet of 13.8% fat and 70.1% carbohydrate for 6 days; there were no changes in the fatty acid composition or restrictions on total energy. Serum lipid profiles at baseline, before and after the HC/LF diet, and LPL polymorphisms were analyzed. After 6 days of the HC/LF diet, TG and the homeostasis model assessment of insulin resistance (HOMA-IR) index were found to increase only in females with S447S. No decrease in HDL-C was noted. In subjects with Hind III polymorphism, increased TG was found in all females but not in males. Increased HDL-C, together with apolipoprotein (apo) AI, was found in male H- carriers but not in males with H+/H+ and females. In conclusion, LPL Ser447Stop and Hind III polymorphisms modified the effects of an HC/LF diet on the serum lipid profiles of a young Chinese population in different ways. Effective strategies for dietary interventions targeted at younger populations should take into account the interplay between genetic polymorphisms, diet, and gender.
p53 is the most frequently mutated gene in all forms of human cancer. It responds to diverse stresses including UVR-induced DNA damage and regulates many downstream genes to initiate cell-cycle arrest, DNA repair or apoptosis. p53 gene variants at codon 11, Pro47Ser and codon 248 (exon 7) were evaluated for bladder cancer (BC) risk in North Indians. In the present study, the above encoding regions in p53 genes were analyzed in a hospital based study in 200 BC and 200 healthy controls age and gender matched and of similar ethnicity. The genotyping was assessed by the polymerase chain reaction restriction fragment length polymorphism technique and statistically evaluated using SPSS software ver. 15.0. A significant association was found with p53 codon 248 polymorphism and BC risk whereas p53 codon 11 and p53 Pro47Ser polymorphism showed no association with BC risk. The individuals carrying the heterozygous genotype (Arg/Trp-Arg/Gln) in the p53 codon 248 polymorphism showed high BC risk (p < 0.001). Combinations with heterozygous and variant genotypes also showed a high risk for BC (p < 0.001). The minor allele (Trp/Gln) carriers of the p53 codon 248 demonstrated a 1.7-fold risk for BC. Furthermore, haplotype analysis revealed that the Glu-Pro-Trp/Gln haplotype is associated with a 1.9-fold risk for BC. A protective role was observed with tumor stage/grade of BC patients with p53 codon 248 (p = 0.003; OR = 0.32). Thus, it is evident from our study that of all the 3 single nucleotide polymorphisms evaluated, only p53 codon 248 (exon7) gene polymorphism has an implication for risk in BC in the North Indian population.
viewing and cross-eyed viewing) for presenting clinical photography. Using the technique, we can grasp 3D structure of various lesions (e.g. tumors, wounds) or surgical procedures (e.g. lymph node dissection, flap) much more easily even without any cost and optical aids compared to 2D photos. Most recently 3D cameras started papers or poster sessions. To create a stereogram, two different pictures were taken based survey. Our survey revealed 57.7% of the doctors/students had acquired the 3D viewing technique and an additional 15.4% could learn parallel viewing with 10 minutes training. Among the subjects capable of 3D views, 73.7% used the parallel views between parallel view users and cross-eyed users. Almost all subjects (94.7%) answered that the technique is useful. Lesions with multiple undulations are a good application. 3D views, especially parallel viewing, are likely to be common and easy may revolutionize presentation of clinical pictures in meetings, educational lectures, or This is the first report investigating the usefulness of a 3D viewing technique (parallel to be commercially available, but they may not be useful for presentation in scientific from the right and left eye views using a digital camera. Then, the two pictures were placed next to one another. Using 9 stereograms, we performed a questionnaire-view technique whereas only 26.3% chose the cross-eyed view. There was no significant difference in the results of the questionnaire about the efficiency and usefulness of 3D enough to consider for practical use in doctors/students. The wide use of the technique manuscripts.
It is unclear whether valganciclovir (VGCV) is effective compared with intravenous ganciclovir (GCV) for preemptive therapy of cytomegalovirus (CMV) infection in living donor liver transplantation (LDLT). A randomized trial was conducted to compare the efficacy of oral VGCV with intravenous GCV for preemptive treatment of CMV infection after LDLT. Patients who developed CMV infection within 6 months after LDLT at Tokyo University Hospital were randomly assigned to the VGCV or GCV group and received either oral VGCV 900 mg/day or intravenous GCV 5 mg/kg twice daily, respectively. The primary endpoint was the treatment success rate. Secondary endpoints were recurrence of CMV infection within 1 year after finishing the treatment, and safety and tolerability of the treatment. Twenty-two patients with CMV infection after LDLT fulfilled the inclusion criteria and were randomly assigned to the oral VGCV group (n = 11) or the intravenous GCV group (n = 11). Treatment success rates were 82% (9 of 11) and 91% (10 of 11) in the VGCV and GCV groups, respectively. One patient in the VGCV group developed recurrence, whereas no patients in the GCV group developed recurrence. All the patients completed the treatment protocol, and no patients in either group dropped out of the study. In conclusion, oral VGCV and intravenous GCV are safe, feasible options for preemptive treatment of CMV infection after LDLT.
Fournier's gangrene (FG) is known as a rapidly progressing necrotizing fasciitis arising from genitourinary and colorectal infections. Misdiagnoses have occurred often because the initial presentation varies and is unclear. We report a case of FG in a 59-year-old man who had undergone a living donor liver transplant. He was in the maintenance phase of immunosuppressant treatment. FG occurred rapidly without symptoms and required prompt and aggressive debridement. Computed tomography demonstrated a small air density in his left testis. Treatment with hyperbaric oxygen therapy followed by intra-operative Gram's staining navigated debridement was additionally performed with general systematic anti-biological therapy and successfully cured the patient. Extra caution should be paid to patients who are maintained on immunosuppressants. Earlier detection and intervention will reduce the rate of mortality to a minimum.